Data-Independent Mass Spectrometry Approach for Screening and Identification of DNA Adducts

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Long-term exposures to environmental toxicants and endogenous electrophiles are causative factors for human diseases including cancer. DNA adducts reflect the internal exposure to genotoxicants and can serve as biomarkers for risk assessment. Liquid chromatography-multistage mass spectrometry (LC-MSn) is the most common method for biomonitoring DNA adducts, generally targeting single exposures and measuring up to several adducts. However, the data often provide limited evidence for a role of a chemical in the etiology of cancer. An "untargeted" method is required that captures global exposures to chemicals, by simultaneously detecting their DNA adducts in the genome; some of which may induce cancer-causing mutations. We established a wide selected ion monitoring tandem mass spectrometry (wide-SIM/MS2) screening method utilizing ultraperformance-LC nanoelectrospray ionization Orbitrap MSn with online trapping to enrich bulky, nonpolar adducts. Wide-SIM scan events are followed by MS2 scans to screen for modified nucleosides by coeluting peaks containing precursor and fragment ions differing by -116.0473 Da, attributed to the neutral loss of deoxyribose. Wide-SIM/MS2 was shown to be superior in sensitivity, specificity, and breadth of adduct coverage to other tested adductomic methods with detection possible at adduct levels as low as 4 per 109 nucleotides. Wide-SIM/MS2 data can be analyzed in a "targeted" fashion by generation of extracted ion chromatograms or in an "untargeted" fashion where a chromatographic peak-picking algorithm can be used to detect putative DNA adducts. Wide-SIM/MS2 successfully detected DNA adducts, derived from chemicals in the diet and traditional medicines and from lipid peroxidation products, in human prostate and renal specimens.

Original languageEnglish (US)
Pages (from-to)11728-11736
Number of pages9
JournalAnalytical Chemistry
Issue number21
StatePublished - Nov 7 2017

Bibliographical note

Funding Information:
*Tel: 612-626-0141; fax: 612-624-3869; e-mail: Rturesky@ (R.J.T.). ORCID Robert J. Turesky: 0000-0001-7355-9903 Funding This research was supported by NIH grants R01 CA220367 (R.J.T.), R01 CA122320 (R.J.T.), R01 ES019564 (R.J.T), R50 CA211256 (P.W.V.), and by the Cancer Center Support Grant CA077598. Notes The authors declare no competing financial interest.

Publisher Copyright:
© 2017 American Chemical Society.


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